Testosterone deficiency, also known as hypogonadism, is gaining recognition among both clinicians and the general population. This article summarizes the findings from a review on the prevalence of testosterone deficiency, as well as the proportion of hypogonadal men who are receiving testosterone treatment.1 While testosterone prescribing has increased lately, as you will find out here, the prevalence of testosterone deficiency far exceeds the prescribing rate; i.e. majority of men with low-T are still not being treated with testosterone therapy.

Key Points

Abbreviations: TT = total testosterone, FT = free testosterone

In population-based studies, the prevalence of hypogonadism in men aged 47-60 years ranges from 2.1% to 12.8%.2-5 The operational definition of hypogonadism used across studies varies considerably:

the Study of Health in Pomerania (SHIP, 1997–2001) (Germany)5 used the most liberal definition of hypogonadism (TT < 300 ng/dL, no symptom criteria) and reported the highest prevalence at 12.8%;

In community-based studies, cut-offs of TT ranging from <200 to <400 ng/dL, with and without low FT, and with and without symptoms, the prevalence of hypogonadism in men aged 54-76 years ranges from 9.5% to 31.2%.6-8

In primary care/screening-based studies, the prevalence of hypogonadism in men aged 53-62 years ranges from 12% to 38.7%:

Using a cut-off for TT <300 ng/dL, prevalence was 19.3%9, 19.8%10, 24.1%11, 24.2%12, and 38.7%13.

Adding symptoms as a criterion, the prevalence decreased from 24.1% to 12%11 and from 24.2% to 20.4%.12

Clinical condition-based studies assessed prevalence of hypogonadism among patients with specific medical conditions. The prevalence of hypogonadism in men aged 53-62 years with morbidities ranges up to 78.8% and varies considerably by medical condition.

The prevalence of hypogonadism in obese patients was found to be 57.7% and 35.6%, using the cut-offs TT <317 ng/dL and FT <78 pg/ml, respectively.14 Another study using the cut-offs TT < 300 ng/dl or FT < 65 pg/ml found the prevalence in obese patients to be 78.8% and 51.5%, respectively.15

The prevalence of hypogonadism in patients with type 2 diabetes ranges from 24.5% to 43% using the cut-off TT <10.4mmol/L (300 ng/dL).16-19 With the cut-off TT <12nmol/L (346 ng/dL), the prevalence is 45%.20

Even after adjusting for age and BMI, the prevalence of subnormal FT levels (<50 pg/ml or 144 pmol/L) in men with type 2 diabetes is higher than in men without (45% versus 33%).21

The prevalence of hypogonadism in patients with the metabolic syndrome ranges from 30 to 35%.22-24

The prevalence of hypogonadism in patients with type 2 diabetes who are also obese or have the metabolic syndrome is 51%21 and 47%25, respectively.

The prevalence of hypogonadism in men with erectile dysfunction is 7%, 23%, 33%, and 47% for testosterone levels of less than 200, less than 300, less than 346, and less than 400 ng/dL, respectively.26

Prevalence of hypogonadism increases with age.
An abrupt increase in hypogonadism prevalence occurred in men aged 45 to 50 yr.26
Using the cut-off < 300 ng/dL, hypogonadism prevalence in primary care patients has been reported to be 34% in men aged 45–54 yr, 40.2% in men aged 55–64 yr, 39.9% in men aged 65–74 yr, 45.5% in men aged 75–84 yr, and 50% in men aged 85 yr and older.13 Every 10-year increase in age confers a 17% increase in risk of hypogonadism.13

Population-based (BACH, Boston Area Community Health)27 and clinical-based (HIM, Health In Men)13 studies report that only 10% to 12% of hypogonadal patients were receiving treatment for hypogonadism.

What is known

Diagnosis of hypogonadism is typically based on the signs and symptoms associated with a deficiency of testosterone levels or its actions, followed by biochemical confirmation of low testosterone levels.28-30 It is well-documented that testosterone levels decline with age in men. After the age of 40 years, total testosterone decreases on average -4 ng/dL ( -0.124 nmol/L) per year31 or 1.6% per year32, and bioavailable testosterone by -2 to -3% per year.32 In older men (over 60 years of age), the average rate of decrement in total testosterone levels has been found to be 110 ng/dL every decade.33 The aging demography will thus cause a large increase in the burden of testosterone deficiency.3

Besides aging alone, lifestyle and different co-morbidities are associated with testosterone deficiency, suggesting that the age-related testosterone decline may be at least partly prevented through the management of potentially modifiable risk factors and health related behaviour.5

What this study adds

The prevalence of hypogonadism and suboptimal testosterone levels is high. It should be noted that most the prevalence numbers listed above are based on the cut-off of 300 ng/dL. Even conservative investigators find a TT cut-off of 12.1 nmol/L (348.3 ng/dl), as opposed to the 300 ng/dl (that some clinicians already think is too high), as the defining lower limit of the testosterone reference range.34 Using this higher cut-off, the prevalence of testosterone deficiency is likely much greater.

Notable is the lack of a standardized definition for hypogonadism diagnosis. As outlined here, the hypogonadism literature reports wide-ranging prevalence based not only on the different populations or subpopulations studied, but also on the use of diverse biochemical cut points or varied choices of symptoms.

Co-morbidities

Besides age per se, obesity, metabolic syndrome, diabetes and dyslipidaemia are risk factors of incident testosterone deficiency.5 This is underscored by a head-to-head comparison of the prevalence of subnormal free testosterone levels in lean, overweight, and obese non-diabetic men, which was found to be 26%, 29% and 40%, respectively (P < 0.001 for trend).21 In lean, overweight, and obese diabetic men, the prevalence of subnormal free testosterone levels is even higher; 44% , 44% and 50%, respectively (P = 0.46 for trend within group and P < 0.05 compared with non-diabetic men).21

The analysis reported here also brings to the attention that in every BMI category, the prevalence of subnormal total testosterone levels is consistently higher than that of free testosterone levels.14 In type 2 diabetics, the reverse is true, i.e. the prevalence of subnormal free testosterone levels is consistently higher than that of total testosterone levels.19,20 One study found that 43% of men with type 2 diabetes had a reduced total testosterone level, while 57% had a reduced free testosterone levels.19 The corresponding numbers in a more recent study are 45% and 61%, respectively.20

Another important finding is the greatly increased prevalence of hypogonadism among men with obesity, type 2 diabetes and/or the metabolic syndrome. The prevalence of obesity and the metabolic syndrome among men aged 20 yr and older is 35.5%35 and 36.1%, respectively.36 26.9% of adults aged 65 years or older have diabetes.37 Because these clinical conditions have become more and more prevalent in all age groups36,38 and have reached epidemic proportions, an alarming increase of non-aging related prevalence of hypogonadism may be expected. It is therefore imperative that clinicians are aware of the impact of co-morbidities on testosterone, and screen their patients for hypogonadism.

Testosterone Prescribing

Testosterone prescribing has increased over the past decade.39-41 From 2001 through 2011, testosterone supplementation among men 40 years or older increased more than 3-fold, from 0.81% in 2001 to 2.91% in 2011. The increase was seen in all age groups. By 2011, 2.29% of men in their 40s and 3.75% of men in their 60s were taking some form of testosterone therapy.39 However, despite an increased use of testosterone therapy, population-based (BACH, Boston Area Community Health) and clinical-based studies (HIM) report that only 10%27 and 12%13 of patients were receiving treatment for hypogonadism, respectively.

It is notable that in the BACH study 40% of men met the Endocrine Society definition for testosterone deficiency (symptoms and/or signs coupled with total testosterone < 300 ng/dL or free testosterone < 5 ng/dL), but only 10% received testosterone therapy.27 In the HIM study, the prevalence of testosterone deficiency (defined by TT <300 ng/dl) was 38.7%. Based on free testosterone (<52 pg/ml) and bioavailable testosterone levels (<95 ng/dl for men <70 years of age and <60 ng/dl for men 70 and older), approximately 40% and 45% of men were hypogonadal, respectively. In this study, a similarly low proportion of men were receiving testosterone therapy (12%). Reasons for this low frequency of hypogonadism treatment may include inadequate knowledge among physicians regarding hypogonadism and uncertainty about diagnostic criteria. Also, patients may not be able to afford therapy in countries that do not provide coverage for testosterone prescriptions.

Another reason is safety concerns. Two world-wide surveys found that concerns about potential side effects of testosterone therapy among doctors is increasing, and that concerns were predominantly related to prostate cancer and cardiovascular disease.42,43 This is not congruent with the growing body of research showing that testosterone therapy is safe for prostate and cardiovascular outcomes.44-46 We have covered prostate and cardiovascular safety issues in previous editorials, see "Testosterone and Prostate Cancer - a paradigm shift" and "Testosterone Treatment and Heart Attack Risk". An assessment of beliefs, knowledge and practice patterns of general practitioners and cardiologists found that testosterone deficiency is not well-understood by general practitioners and cardiologists, and that these key clinicians lack knowledge on its deleterious cardiovascular effects.47

Thus, it is critical to look at both sides of the prescribing - need equation; citing increases in testosterone prescribing without looking at hypogonadism prevalence and men's health status will give a misleading picture. The review reported here indicates that the reported increase in testosterone prescribing still does not offer treatment for the vast majority of men who need it for their health and wellbeing.